title: Genotypic analysis of the V3 region of HIV from virologic nonresponders to maraviroc-containing regimens reveals distinct patterns of failure.
abstract: Changes in HIV tropism from R5 to non-R5 or development of drug resistance is often associated with virologic failure in patients treated with maraviroc, a CCR5 antagonist. We sought to examine changes in HIV envelope sequences and inferred tropism in patients who did not respond to maraviroc-based regimens. We selected 181 patients who experienced early virologic failure on maraviroc-containing therapy in the MOTIVATE trials. All patients had R5 HIV by the original Trofile assay before entry. We used population-based sequencing methods and the geno2pheno algorithm to examine changes in tropism and V3 sequences at the time of failure. Using deep sequencing, we assessed whether V3 sequences observed at failure emerged from preexisting subpopulations. From population genotyping data at failure, 90 patients had R5 results, and 91 had non-R5 results. Of the latter group, the geno2pheno false-positive rate (FPR) value fell from a median of 20 at screening to 1.1 at failure. By deep sequencing, the median percentage of non-R5 variants in these patients rose from 1.4% to 99.5% after a median of 4 weeks on maraviroc. In 70% of cases, deep sequencing could detect a pretreatment CXCR4-using subpopulation, which emerged at failure. Overall, there were two distinct patterns of failure of maraviroc. Patients failing with R5 generally had few V3 substitutions and low non-R5 prevalence by deep sequencing. Patients with non-R5 HIV who were failing developed very-high-prevalence non-R5 HIV (median, 99%) and had very low geno2pheno values.
authors.affiliation: BC Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada.
authors.forename: Luke C
authors.initials: LC
authors.lastname: Swenson
authors.forename: Celia K S
authors.initials: CK
authors.lastname: Chui
authors.forename: Chanson J
authors.initials: CJ
authors.lastname: Brumme
authors.forename: Dennison
authors.initials: D
authors.lastname: Chan
authors.forename: Conan K
authors.initials: CK
authors.lastname: Woods
authors.forename: Theresa
authors.initials: T
authors.lastname: Mo
authors.forename: Winnie
authors.initials: W
authors.lastname: Dong
authors.forename: Doug
authors.initials: D
authors.lastname: Chapman
authors.forename: Marilyn
authors.initials: M
authors.lastname: Lewis
authors.forename: James F
authors.initials: JF
authors.lastname: Demarest
authors.forename: Ian
authors.initials: I
authors.lastname: James
authors.forename: Simon
authors.initials: S
authors.lastname: Portsmouth
authors.forename: James
authors.initials: J
authors.lastname: Goodrich
authors.forename: Jayvant
authors.initials: J
authors.lastname: Heera
authors.forename: Hernan
authors.initials: H
authors.lastname: Valdez
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D065100:CCR5 Receptor Antagonists / Q000627:therapeutic use; D003510:Cyclohexanes / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression; D005838:Genotype; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics; D023581:HIV Fusion Inhibitors / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D017211:Treatment Failure; D014230:Triazoles / Q000627:therapeutic use; D056189:Viral Tropism
chemical_list: D065100:CCR5 Receptor Antagonists; C584933:CCR5 protein, human; C527276:CXCR4 protein, human; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D014230:Triazoles; D000077592:Maraviroc